Several processes for producing Menadione are known in the art.
One common technique is the oxidation of 2-methyl-naphthalene by using sodium dichromate in aqueous sulfuric acid solution. In this case, despite the low selectivity for the 2-isomer, the high degree of destruction of the 6-isomer due to the added excess hexavalent chromium results in a final product containing a high content of Menadione. For example, the U.S. Pat. No. 3,751,437 discloses that although the reaction selectivity for the 2-methyl-1,4-naphthoquinone is not very high (50-53%), the final product is mainly composed of Menadione (94-97%), some unreacted 2-methyl-naphthalene (2-MNA) and small amounts of undefined impurities. The main drawbacks of this process are the very low selectivity of the reaction for the formation of the 2-methyl-1,4-naphthoquinone isomer, the need for excessive amounts of highly toxic hexavalent chromium as oxidizing agent and the creation of significant amounts of basic chromium sulfate as the reaction byproduct.
In order to resolve these problems related to the process described above, the use of other oxidizing agents has been proposed in the state of the art. However, in all the proposed alternatives using other oxidizing agents, the 6 isomer is present in the final product mixture at much higher ratios. For example, when hydrogen peroxide (in the presence of a methyltrioxorhenium catalyst) is used to oxidize 2-MNA, the final methyl-quinones are composed of 86% of 2 isomer and 14% of 6 isomer i.e. a ratio of 2 to 6 isomer of 7:1 (W. Adam, W. A. HerrmannJ. Lin, C. R. Saha-Moeller, R. W. Fischer and J. D. G. Correia, <<Homogeneous catalytic oxidation of arenes and a new synthesis of vitamin K3, Angew. Chem. Int. Ed. Engl., 33, p. 2475-2477 (1994)). In another example, when 2-MNA is oxidized using ammonium persulfate (in the presence of catalytic amounts of cerium ammonium sulfate and silver nitrate), the ratio of the 2 to 6 isomer was around 3:1 (J. Skarzewski, <<Cerium catalyzed persulfate oxidation of polycyclic aromatic hydrocarbons to quinones, Tetrahedron, 40, p 4997-5000 (1984)). The use of ceric sulfate as oxidant in an acetonitrile-sulfuric acid mixture also resulted in relatively high amounts of 6 isomer in the final product, i.e. 2 to 6 isomer ratio of 6.5:1 (IN 157224 A).
While the use of highly toxic hexavalent chromium as well as the creation of a considerable amount of the basic chromium sulfate is avoided in the methods of the state of the art cited above, the final reaction mixture contains significant amounts of the 6 isomer which is quite difficult to separate from the desired 2 isomer due to the similar properties of the two isomers. There are different proposals in the art to separate the two isomers. The most relevant strategies are:                Avoiding the creation of the 6 isomer by using a different raw material and a Diels-Alder reaction        Separating the undesired 6 isomer by its selective transformation in methyl-anthraquinone        Treating the final product mixture with an aqueous bisulfite solution to separate the 6 isomer        
However, all of these strategies suffer from major disadvantages:
The U.S. Pat. No. 5,770,774 proposes to avoid making the 6-isomer by using 2-methyl-1,4-benzoquinone as raw material. This product is reacted with 1,3-butadiene in a Diels-Alder reaction to make 2-methyl-4-a,5,8,8a-tetrahydro-1,4-naphthoquinone, which is then oxidized to 2-methyl-1,4-naphthoquinone.
There are several problems associated with this procedure. For one, the raw material 2-methyl-1,4-benzoquinone is expensive and not readily available in large amounts. Furthermore, 1,3-butadiene is a highly toxic agent. Finally, the reaction presupposes the presence of a Lewis acid catalyst in order to proceed.
The U.S. Pat. No. 5,329,026 discloses the reaction of 6-methyl-1,4-naphthoquinone with 1,3-butadiene to make 1,4,4a,9a-tetrahydro-6-methylanthraquinone. The latter molecule can then be oxidized to the methyl-anthraquinone by adding sodium hydroxide and bubbling air as oxidation agent. The 2-methyl-1,4-naphthoquinone isomer hardly undergoes the same Diels-Alder reaction with the 1,3-butadiene due to the steric hindrance and difference in electron density.
In addition to the problems of the previous process (use of highly toxic 1,3-butadiene), there are further disadvantages associated with this process: it has to be conducted at high temperatures (ca. 120° C.) and high reaction pressure, thus necessitating the use of expensive apparatuses like autoclaves with a high energy consumption. Furthermore, the reaction time is very long (up to 4 hours).
The Japanese Application 60252445 A discloses the treatment of the final product mixture with an aqueous bisulfite solution to separate the 6-isomer. The organic solvent containing the starting and the final products of the 2-MNA oxidation reaction is first cooled down to precipitate part of the 2-MNQ formed during the oxidation. The remaining solvent phase is then treated with a bisulfite solution to extract most of the 6 isomer as well as part of the 2-isomer as bisulfite adduct that is soluble in the aqueous phase. Due to the fact that the 6-isomer reacts much faster than the 2-isomer, the remaining solvent phase presents a much higher ratio of 2- to 6-isomer. The organic phase is cooled down to obtain 2-MNQ crystals (94% purity). The solvent filtrate is treated in a selective bisulfidation step in which typically 25-30% of 2-MNQ is extracted in order to reach around 90% 6-MNQ extraction rates (this represents around 8 to 10% of the total 2-MNQ produced during the oxidation step). The aqueous solution containing bisulfite adducts of 2-MNQ and 6-MNQ becomes a waste.
The 2-MNQ crystals from the first crystallization are dissolved in the organic phase and recrystallized (around 65% precipitation yield). The 2-MNQ produced contains still on average 2% of the 6-MNQ isomer. The aqueous phase of the oxidation step is extracted in an extraction step using extra solvent that is then combined with the solvent from the second crystallization step. The obtained mixture needs to go through an additional step of solvent evaporation in order to concentrate the organic phase before its use in the next oxidation cycle. The overall process is presented in FIG. 1.
There are various drawbacks associated with the process as described above.
Firstly, significant amounts of 2-MNQ (around 8% in first cycle of example 3 and around 10% overall assuming a yield of 2-MNQ crystals of 55% and the assumed 65% overall yield for a cerium sulfate process) are lost in the bisulfidation step and not recovered.
Second, the produced 2-MNQ is not of a very high purity after the first crystallization due to the fact that the selective bisulfidation is not carried out before this crystallization. The purity of 2-MNQ even after the second (final) crystallization is less than 98% due to the fact that 10% of the original 6-MNQ is still left in the solvent after the selective bisulfidation (a higher extraction rate results in excessively high 2-MNQ extraction and loss rates).
Third, an important part of the produced 2-MNQ is recycled back to the oxidation reactor (around 35% in the example 3) which may result in overoxidation and further losses of 2-MNQ.
Fourth, the organic phase of the extraction of the aqueous phase from the oxidation step is mixed with the filtrate from step 4 (after the second crystallization) and before it gets recycled it needs to be concentrated by evaporation. This adds additional steps and costs to the process.
Chengying et al later proposed an approach similar to the Japanese patent based on using 2-MNQ precipitation, followed by bisulfidation reaction and finally the re-dissolution of the precipitated 2-MNQ in the initial solvent phase to separate the 6 isomer from the 2 isomer (<<Process improvement on synthesis of 2-methyl-1,4-naphthoquinone>>, Song Chengying, Wang Liucheng, Zhao Jianhong and Xu Haisheng, Chemical Reaction Engineering and Technology, vol. 23, No. 4, Aug. 2007). Contrary to the Japanese patent approach, the ratio of 2-MNQ to solvent proposed by these authors seems very low (a weight ratio of solvent to 2-MNQ of 4 compared to between 12 and 120 in the case of the Japanese patent). At this ratio, around 95% of the 2-MNQ formed will precipitate at the first crystallization step. However, this will be accompanied also by a high rate of 6-MNQ precipitation resulting in a low purity of the first 2-MNQ crystals. Therefore, despite high extraction rates of dissolved 6-MNQ at the bisulfidation step, once the first 2-MNQ crystals are re-dissolved in the solvent phase after the selective bisulfidation step, the residual 6-MNQ in the final 2-MNQ obtained in the second crystallization step should be significantly higher than the 0.5% claimed by the authors resulting in a relatively low purity of final 2-MNQ product.
Problem Underlying the Invention
The technical problem to be solved is to devise a method for producing Menadione and Menadione derivatives which overcomes the disadvantages of the processes disclosed in the state of the art.
Specifically, the process to produce Menadione and Menadione derivatives shall avoid the use of aggressive oxidizing agents like hexavalent chromium, without compromising the purity of the Menadione or its derivatives.
Furthermore, the envisaged process shall avoid the application of high temperatures and pressures as well as toxic reagents.
Finally, the envisaged process shall achieve a selectivity, yield and purity that is at least comparable, if not better than what is currently known in the art.